Acta Naturae最新文献

The Rurikids were the reigning house of Rus', its principalities and, ultimately the Tsardom of Russia, for seven centuries: from the IX to the end of the XVI century. According to the Primary Chronicle (the Tale of Bygone Years), the main chronicle of Rus', the Rurik dynasty was founded by the Varangian prince Rurik, invited to reign in Novgorod in 862, but still there is no direct genetic evidence of the origin of the early Rurikids. This research, for the first time, provides a genome-wide paleogenetic analysis of bone remains belonging to one of the Rurikids, Prince Dmitry Alexandrovich (?-1294), the son of the Grand Prince of Vladimir Alexander Yaroslavich Nevsky (1221-1263). It has been established that his Y chromosome belongs to the N1a haplogroup. Most of the modern Rurikids, according to their genealogies, belonging to the N1a haplogroup, have the most similar variants of Y chromosomes to each other, as well as to the Y chromosome of Prince Dmitry Alexandrovich. Genome-wide data of the medieval and modern Rurikids unequivocally indicates that they belong to the N1a haplogroup of the Y chromosome, starting at least from the XI century (since the time of Prince Yaroslav the Wise). All the other alleged Rurikids, both ancient and modern, being carriers of other haplogroups (R1a, I2a), possess high heterogeneity of the sequence of Y chromosomes, meaning that we cannot confirm their common ancestry. The most probable ancestors of Prince Dmitry Alexandrovich in the male line were the men who left the burial ground Bolshoy Oleny Island on the coast of the Kola Peninsula about 3,600 years ago. The reconstruction of the genome of Prince Dmitry Alexandrovich indicates the contribution of three ancestral components to his origin: (1) the early medieval population of the east of Scandinavia from the island of Oland, (2) representatives of the steppe nomadic peoples of the Eurasian steppes of the Iron Age or the early medieval population of central Europe (steppe nomads from the territory of Hungary), and (3) the ancient East-Eurasian component. Reliable statistics were also obtained when the Scandinavians were replaced with the Medieval Russian Slavic populations of the XI century. Thus, for the first time, we have shown the complex nature of interethnic interactions in the formation of the nobility of medieval Rus' on the example of the ancient Rurikid.

Tumor cells endure continuous DNA replication stress, which opens the way to cancer development. Despite previous research, the prognostic implications of DNA replication stress on lung adenocarcinoma (LUAD) have yet to be investigated. Here, we aimed to investigate the potential of DNA replication stress-related genes (DNARSs) in predicting the prognosis of individuals with LUAD. Differentially expressed genes (DEGs) originated from the TCGA-LUAD dataset, and we constructed a 10-gene LUAD prognostic model based on DNARSs-related DEGs (DRSDs) using Cox regression analysis. The receiver operating characteristic (ROC) curve demonstrated excellent predictive capability for the LUAD prognostic model, while the Kaplan-Meier survival curve indicated a poorer prognosis in a high-risk (HR) group. Combined with clinical data, the Riskscore was found to be an independent predictor of LUAD prognosis. By incorporating Riskscore and clinical data, we developed a nomogram that demonstrated a capacity to predict overall survival and exhibited clinical utility, which was validated through the calibration curve, ROC curve, and decision curve analysis curve tests, confirming its effectiveness in prognostic evaluation. Immune analysis revealed that individuals belonging to the low-risk (LR) group exhibited a greater abundance of immune cell infiltration and higher levels of immune function. We calculated the immunopheno score and TIDE scores and tested them on the IMvigor210 and GSE78220 cohorts and found that individuals categorized in the LR group exhibited a higher likelihood of deriving therapeutic benefits from immunotherapy intervention. Additionally, we predicted that patients classified in the HR group would demonstrate enhanced sensitivity to Docetaxel using anti-tumor drugs. To summarize, we successfully developed and validated a prognostic model for LUAD by incorporating DNA replication stress as a key factor.

Frequent chromosomal abnormalities are a distinctive feature of early embryonic development in mammals, especially humans. Aneuploidy is considered as a contributing factor to failed embryo implantation and spontaneous abortions. In the case of chromosomal mosaicism, its effect on the potency of embryos to normally develop has not been sufficiently studied. Although, a significant percentage of chromosomal defects in early human embryos are currently believed to be associated with the features of clinical and laboratory protocols, in this review, we focus on the biological mechanisms associated with chromosomal abnormalities. In particular, we address the main events in oocyte meiosis that affects not only the genetic status of an unfertilized oocyte, but also further embryo viability, and analyze the features of first cleavage divisions and the causes of frequent chromosomal errors in early embryonic development. In addition, we discuss current data on self-correction of the chromosomal status in early embryos.

Among the nonvirion proteins of the vaccinia virus (VACV), a 94-kDa long protein is most abundantly present; the protein is a truncated form of the 150-kDa A-type inclusion (ATI) protein of the cowpox virus encoded by the ati gene. This VACV protein does not form intracellular ATIs, being as it is a major immunogen upon infection/immunization of humans or animals with the VACV. Antibodies specific to this protein are not virus-neutralizing. The present study focused on the effect of the production of this nonstructural major immunogenic VACV protein on the manifestation of pathogenicity and immunogenicity of the virus in the BALB/c mouse model of infection. In order to introduce a targeted deletion into the VACV LIVP genome, the recombinant integration/deletion plasmid pΔati was constructed and further used to generate the recombinant virus LIVPΔati. The pathogenicity of the VACV LIVP and LIVPΔati strains was studied in 3-week-old mice. The mice were intranasally infected with the viruses at a dose of 107 pfu; 50% of the animals infected with the parent LIVP strain died, while infection with the LIVPΔati strain led to the death of only 20% of the mice. Intradermal vaccination of mice aged 6- weeks with the LIVPΔati virus statistically significantly increased the production of VACV-specific IgG, compared to that after intradermal vaccination with VACV LIVP. Meanwhile, no differences were noted in the cell-mediated immune response to the vaccination of mice with VACV LIVP or LIVPΔati, which was assessed by ELISpot according to the number of splenocytes producing IFN-γ in response to stimulation with virus-specific peptides. Intranasal infection of mice with lethal doses of the cowpox virus or the ectromelia virus on day 60 post-immunization with the studied VACV variants demonstrated that the mutant LIVPΔati elicits a stronger protective response compared to the parent LIVP.

The leukocyte common antigen CD45 is a receptor tyrosine phosphatase and one of the most prevalent antigens found on the surface of blood cells. CD45 plays a crucial role in the initial stages of signal transmission from receptors of various immune cell types. Immunodeficiency, autoimmune disorders, and oncological diseases are frequently caused by gene expression disorders and imbalances in CD45 isoforms. Despite extensive research into the structure and functions of CD45, the molecular mechanisms behind its role in transmitting signals from T-cell receptors and chimeric antigen receptors remain not fully understood. It is of utmost importance to comprehend the structural features of CD45 and its function in regulating immune system cell activation to study oncological diseases and the impact of CD45 on lymphocytes and T cells modified by chimeric antigen receptors.

Tumor cells have the capacity to create an adenosine-rich immunosuppressive environment, which can interfere with antitumor immunotherapy. Approaches are currently being developed with a view to suppressing the production of adenosine or its signals. Such approaches include the use of antibodies to inhibit CD39, CD73, and adenosine-receptor antagonists. However, the abundance of enzymatic pathways that control the ATP-adenosine balance, as well as the still poorly understood intracellular adenosine regulation, makes the hoped-for success unlikely. In the present study, the enzyme adenosine kinase (ADK) needed to convert adenosine to adenosine monophosphate, thereby regulating its levels, was investigated. To do so, peripheral blood samples from patients with colorectal cancer (CRC) (n = 31) were collected with blood samples from healthy donors (n = 17) used as controls. ADK gene expression levels and those of its long (ADK-L) and short (ADK-S) isoforms were measured. The relationship between the levels of ADK gene expression and that of CD39, CD73, and A2aR genes was analyzed. It turned out that in the group of CRC patients (stages III-IV), the level of ADK-L mRNA was lower (p < 0.0011) when compared to that of the control. For the first time, an average correlation was found between the level of expression of CD39 and ADK-S (r = -0.468 at p = 0.043) and between CD73 and ADK-L (r = 0.518 at p = 0.0232) in CRC patients. Flow cytometry was used to assess the content of CD39/CD73-expressing CD8⁺, CD4⁺ and Treg lymphocytes, as well as their relationship with the level of ADK gene expression in CRC patients. But no significant correlations were found.

Developing liver disease treatments, in which fibrosis is a key pathogenetic link, still remains an urgent problem in hepatology. In the present study, the level of mmp-9 mRNA expression and the number of FAP+, α-SMA+, CD45+ cells were analyzed at nine time points of fibrosis and cirrhosis. It was found that in the case of liver fibrosis, the choice of the optimal reference gene depended on the stage of fibrogenesis. When studying the specific stages rather than the entire process in a long-term experiment, it was shown that choosing an optimal reference gene has to be done additionally. In this case, the mmp-9 mRNA expression level should be considered as a marker of liver fibrosis initiation and development but not as that of cirrhosis progression. In the liver, two morphologically heterogeneous populations of myofibroblasts were simultaneously identified as able to synthesize various types of immunohistochemical markers. It was found that the FAP+ cells were the main contributor to the development of portal fibrosis and the initial stages of bridging fibrosis. In the selected experimental model, fibrosis initiation and the development stages preceding parenchyma restructuring were accompanied by a low level of inflammation.

Since the addition of the CRISPR/Cas9 technology to the genetic engineering toolbox, the problems of low efficiency and off-target effects hamper its widespread use in all fields of life sciences. Furthermore, essential gene knockout usually results in failure and it is often not obvious whether the gene of interest is an essential one. Here, we report on a new strategy to improve the CRISPR/Cas9 genome editing, which is based on the idea that editing efficiency is tightly linked to how essential the gene to be modified is. The more essential the gene, the less the efficiency of the editing and the larger the number of off-targets, due to the survivorship bias. Considering this, we generated deletions of three essential genes in Drosophila: trf2, top2, and mep-1, using fly strains with previous target gene overexpression ("pre-rescued" genetic background).